Isoxazolidine derivatives

ABSTRACT

Glucocorticosteroids that are derivatives of isoxazolidine are useful as anti-inflammatory and antiallergic compounds of the glucocorticosteroid series.

CROSS REFERENCES TO RELATED APPLICATIONS

This application claims priority to European Patent Application No.12184286.8, filed on Sep. 13, 2012, which is incorporated herein byreference in its entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to novel anti-inflammatory andantiallergic compounds of the glucocorticosteroid series, methods ofpreparing such compounds, pharmaceutical compositions comprising such acompound, combinations containing such a compound, and therapeutic usesof such a compound. More particularly, the present invention relates toglucocorticosteroids that are isoxazolidine derivatives.

2. Discussion of the Background

Corticosteroids are potent anti-inflammatory agents, able to decreasethe number, activity and movement of inflammatory cells. Corticosteroidsare commonly used to treat a wide range of chronic and acuteinflammatory conditions including asthma, chronic obstructive pulmonarydisease (COPD), allergic rhinitis, rheumatoid arthritis, inflammatorybowel disease and autoimmune diseases. Corticosteroids mediate theireffects through the glucocorticoid receptor (GR). The binding ofcorticosteroids to GR induces its nuclear translocation which, in turn,affects a number of downstream pathways via DNA-binding-dependent (e.g.transactivation) and -independent (e.g. transespression) mechanisms.

Corticosteroids for treating chronic inflammatory conditions in the lungsuch as asthma and COPD are currently administered through inhalation.One of the advantages of employing inhaled corticosteroids (ICS) is thepossibility of delivering the drug directly at site of action, therebylimiting systemic side-effects, thus resulting in a more rapid clinicalresponse and a higher therapeutic ratio.

Although ICS treatment can afford important benefits, especially inasthma, it is important to minimize ICS systemic exposure which leads tothe occurrence and severity of unwanted side effects that may beassociated with chronic administration. Moreover, the limited durationof action of ICS currently available in the clinical practicecontributes to suboptimal management of the disease. While the inhalertechnology is the key point to target the lung, the modulation of thesubstituents on the corticosteroids molecular scaffold is important forthe optimization of pharmacokinetic and pharmacodynamic properties inorder to decrease oral bioavailability, confine pharmacological activityonly in the lung (prodrugs and soft drugs) and increase systemicclearance. Moreover, long lasting ICS activity in the lung is highlydesirable as once daily administration of ICS would allow the reductionof the frequency of administration and, thus, substantially improvepatient compliance and, as a result, disease management and control. Insum, there is a pressing medical need for developing ICS with improvedpharmacokinetic and pharmacodynamic characteristics.

Glucocorticoids isoxazolidine derivatives are for instance described inWO 2006/005611, GB 1578446 and in “Synthesis and topicalanti-inflammatory activity of some steroidal [16α,17α-d] isoxazolidines”(J. Med. Chem., 25, 1492-1495, 1982), all of which are incorporatedherein by reference in their entireties. Some glucocorticoidisoxazolidine derivatives are also described in the co-pending patentapplications WO 2011/029547, WO 2012/123482, and WO 2012/123493, all ofwhich are incorporated herein by reference in their entireties.

However, there remains a need for glucocorticosteroid with improvedpharmacological properties.

SUMMARY OF THE INVENTION

Accordingly, it is one object of the present invention to provide novelanti-inflammatory and antiallergic compounds of the glucocorticosteroidseries.

It is another object of the present invention to provide novel processesfor the preparation of such compounds.

It is another object of the present invention to provide novelcompositions which comprising such a compound.

It is another object of the present invention to provide novel methodsof treating certain diseases and conditions by administering such acompound.

It is another object of the present invention to provide novelcombinations of such a compound with another pharmaceutical activeingredient for the treatment of respiratory disorders, such asbeta2-agonists, antimuscarinic agents, mitogen-activated protein kinases(P38 MAP kinase) inhibitors, nuclear factor kappa-B kinase subunit beta(IKK2) inhibitors, human neutrophil elastase (HNE) inhibitors,phosphodiesterase 4 (PDE4) inhibitors, leukotriene modulators,non-steroidal anti-inflammatory agents (NSAIDs), antitussive agents,mucus regulators, mucolytics, expectorant/mucokinetic modulators,peptide mucolytics, antibiotics, inhibitors of JAK, SYK inhibitors,inhibitors of PI3 Kdelta or PI3 Kgamma, M3-antagonists/beta2-agonists(MABA), and M3-antagonists/PDE4-inhibitors (MAPI).

These and other objects, which will become apparent during the followingdetailed description, have been achieved by the inventors' discoverythat compounds of formula (I) and salts thereof are useful asanti-inflammatory and antiallergic compounds of theglucocorticosteroids.

Surprisingly, it has been found that the compounds of the presentinvention show improved pharmacokinetic or pharmacodynamiccharacteristics, such as systemic exposure, selectivity and duration ofaction.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

In particular, the invention is directed to compounds of general formula(I):

wherein

R₁ is linear or branched (C₁-C₁₆)alkyl, linear or branched(C₂-C₁₈)alkenyl, —OR₆, aryl, aryl(C₁-C₁₆)alkyl, —SR₆, —N(R₄)(R₅),(C₃-C₈)cycloalkyl, (C₃-C₈)heterocycloalkyl, or heteroaryl, whereinoptionally one or more hydrogen atoms are replaced by (C₁-C₆)alkyl, andwherein R₄ and R₅ are independently H or linear or branched(C₁-C₆)alkyl, and R₆ is linear or branched (C₁-C₁₆)alkyl;

R₂ is aryl optionally substituted by one or more halogen atoms; andpharmaceutically acceptable salts thereof.

In the present description, unless otherwise provided, the term“halogen” includes fluorine, chlorine, bromine and iodine atoms.

The term “(C₁-C₁₆)alkyl” refers to linear or branched chain alkyl groupswherein the number of carbon atoms is from 1 to 16. Examples of saidgroups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, ethyl-butyl,propyl-butyl, methyl-butyl, ethyl-methyl-propyl, hexadecyl, undecyl,dodecyl, tridecyl, quaterdecyl, quindecyl, hexadecyl, and the like.

The expression “(C₂-C₁₈)alkenyl” refers to linear or branched carbonchains with one or more double bonds, wherein the number of carbon atomsis from 2 to 18. Examples of said groups include ethenyl, propenyl,butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl,undecenyl, dodecenyl, tridecenyl, quaterdecenyl, quindecenyl,hexadecenyl, heptadecenyl and the like.

The expression “(C₃-C₈)cycloalkyl” refers to mono- or bi-cycloaliphatichydrocarbon groups with from 3 to 8 carbon atoms. Examples includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,bicyclo[2.2.1]hept-2-yl, and the like.

The expression “(C₃-C₈)heterocycloalkyl” refers to (C₃-C₈)cycloalkylgroups, in which at least one ring carbon atom is replaced by aheteroatom or heteroaromatic group (e.g. N, NH, S or O). Examplesinclude piperazinyl, thiazolidinyl, pyrrolidinyl, piperidinyl,morpholinyl, and the like.

The expression “aryl” refers to mono-, bi- or tri-cyclic ring systemswhich have 6 to 20 ring atoms, preferably from 6 to 15 and wherein atleast one ring is aromatic. Examples of suitable aryl monocyclic systemsinclude benzene radical (phenyl) and the like. Examples of suitable arylbicyclic systems include naphthalene (naphthyl), biphenylene(biphenylenyl) radicals and the like. Examples of suitable aryltricyclic systems include fluorine radical (fluorinyl) and the like.

The expression “aryl(C₁-C₆)alkyl” refers to (C₁-C₆)alkyl groups furthersubstituted by aryl.

As used herein, the term “heteroaryl” refers to mono-, bi- or tricyclicring system which have 5 to 20 ring atoms, preferably from 5 to 15, inwhich at least one ring is aromatic and in which at least one ring atomis a heteroatom or heteroaromatic group (e.g. N, NH, S or O).

Examples of suitable heteroaryl monocyclic systems include thiophene(thiophenyl), pyrrole (pyrrolyl), pyrazole (pyrazolyl), imidazole(imidazolyl), isoxazole (isoxazolyl), oxazole (oxazolyl), isothiazole(isothiazolyl), thiazole (thiazolyl), pyridine (pyridinyl),imidazolidine (imidazolidinyl), piperidine (piperidinyl), piperazine(piperzazinyl), and furan (furanyl) radicals such as tetrahydrofuran(tetrahydrofuranyl) and the like.

Examples of suitable heteroaryl bicyclic systems include purine(purinyl), pteridine (pteridinyl), benzotriazole (benzotriazolyl),quinolone (quinolinyl), isoquinoline (isoquinolinyl), indole (indolyl),isoindole (isoindolyl), benzofuran (benzofuranyl), benzodioxane(benzodioxaneyl), benzothiophene (benzothiphenyl) radicals and the like.

It will be apparent to those skilled in the art that compounds ofgeneral formula (I) contain asymmetric centers at least at the positions4a, 4b, 5, 6a, 6b, 9a, 10a, 10b and therefore may exist as many opticalstereoisomers and mixtures thereof. Therefore the invention is alsodirected to all of these forms and mixtures thereof.

Preferred compounds are those of general formula (I) wherein thestereochemistry of stereogenic carbon atoms is as reported in formula(I′) below, in which the absolute configuration is assigned on the basisof Cahn-Ingold-Prelog nomenclature based on groups' priorities

and wherein the meanings of R₁ and R₂ are as defined above.

In one preferred embodiment, for compounds of formula (I′), the absoluteconfiguration at asymmetric center 4a is (S), at 4b is (R), at 5 is (S),at 6a is (S), at 6b is (R), at 9a is (S), at 10a is (S), at 10b is (S)and at 12 is (S).

Compounds of general formula (I) may form acid addition salts,particularly with pharmaceutically acceptable acids. Pharmaceuticallyacceptable acid addition salts of the compounds of formula (I), thusencompassing also those of formula (I′), include salts with inorganicacids, for example hydrohalogen acids such as hydrofluoric,hydrochloric, hydrobromic or hydroiodic; nitric, sulfuric, phosphoric;and organic acids, for example aliphatic monocarboxylic acids such asformic, acetic, trifluoroacetic and propionic; aliphatic hydroxyl acidssuch as lactic, citric, tartaric or malic; dicarboxylic acids such asmaleic, fumaric, oxalic or succinic; aromatic carboxylic acids such asbenzoic; aromatic hydroxy acids and sulfonic acids. These salts may beprepared from compounds of formula (I) or (I′) by known salt-formingprocedures.

It is to be understood that all preferred groups or embodimentsdescribed herebelow for compounds of formula (I) may be combined amongeach other and apply as well mutatis mutandis.

A preferred group of compounds of general formula (I) or (I′) is thatwherein R₁ is linear or branched (C₁-C₁₆)alkyl, linear or branched(C₂-C₁₈)alkenyl, —OR₆, aryl, aryl(C₁-C₁₆)alkyl, —SR₆, —N(R₄)(R₅),(C₃-C₈)cycloalkyl, (C₃-C₈)heterocycloalkyl, or heteroaryl, whereinoptionally one or more hydrogen atoms are replaced by (C₁-C₆)alkyl andwherein R₄ and R₅ are independently H or linear or branched (C₁-C₆)alkyland R₆ is linear or branched (C₁-C₁₆)alkyl; and R₂ is aryl optionallysubstituted by one or more halogen atoms.

Even more preferred within this group are the compounds of generalformula (I) or (I′) wherein R₁ is selected from the group consisting ofmethyl, isopropyl, ethyl, quindecyl, butyl, hexyl, heptadecenyl,methoxy, methylsulfanyl, isobutyl, isopentyl, tertbutyl, methylamino,dimethylamino, phenyl, cyclopropyl, cyclopentyl, methylpropanoxy,benzyl, piridyl, piperazinyl, piperidinyl, pyrrolidinyl, thiazolidinyl,and furyl; and R₂ is p-chlorophenyl.

Hereinafter, compounds of formula (I) and (I′) and theirpharmaceutically acceptable salts and solvates are referred to as“compounds of the present invention”.

Examples of preferred compounds of the invention are:

Compound Chemical Name 1 Isobutyric acid2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethyl ester 3 Propionic acid2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethyl ester 4 Hexadecanoic acid2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethyl ester 5 Octadec-9-enoicacid 2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethyl ester 6 Pentanoic acid2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethyl ester 7 Acetic acid2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethyl ester 8 Benzoic acid2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethyl ester 9 Methyl carbonate(Methyl formate) 2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethyl ester) 10 S-methylcarbonothioate (or S-methyl methanethioate) 2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethyl ester 11 3-Methylbutanoicacid 2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethyl ester 12 Pivalic acid2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethyl ester 13 2-Phenylaceticacid 2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethyl ester 14Furan-2-carboxylic acid 2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethyl ester 15Cyclopentane-carboxylic acid 2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethyl ester 16Cyclopropane-carboxylic acid 2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethyl ester 17 Isonicotinicacid 2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethyl ester 18 Isobutyl methylcarbonate 2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethyl ester 19 Hexyl carbonate2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethyl ester) 20 Dimethyl2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethyl carbamate 21 Methyl2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethyl carbamate 22Piperazine-1-carboxylic acid 2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethyl ester 23Thiazolidine-4-carboxylic acid 2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethyl ester 24 Proline,2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4^(a),6^(a)-dimethyl-2-oxo-2,4a,4b,5,6,6^(a),8,9,9^(a),10,10^(a),10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethyl ester 25Piperidine-4-carboxylic acid, 2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethyl ester

According to analogous procedures and methods herein described, thepreferred compounds of the invention from the list below reported, maybe obtained:

Compound Chemical Name 26 Butanoic acid2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethyl ester 27 Butanoic acid,2-methyl-, 2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethyl ester 28Cyclobutanecarboxylic acid, 2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4^(a),6^(a)-dimethyl-2-oxo-2,4^(a),4b,5,6,6^(a),8,9,9^(a),10,10^(a),10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethyl ester 29Cyclohexanecarboxylic acid, 2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4^(a),6^(a)-dimethyl-2-oxo-2,4^(a),4b,5,6,6^(a),8,9,9^(a),10,10^(a),10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethyl ester 302-Thiophenecarboxylic acid, tetrahydro-, 2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4^(a),6^(a)-dimethyl-2-oxo-2,4^(a),4b,5,6,6^(a),8,9,9^(a),10,10^(a),10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethyl ester 312H-thiopyran-4-carboxylic acid, tetrahydro-, 2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4^(a),6^(a)-dimethyl-2-oxo-2,4^(a),4b,5,6,6^(a),8,9,9^(a),10,10^(a),10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethyl ester 32Cyclopentanecarboxylic acid, 2,5-dimethyl-, 2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4^(a),6^(a)-dimethyl-2-oxo-2,4^(a),4b,5,6,6^(a),8,9,9^(a),10,10^(a),10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethyl ester 33Cyclohexanecarboxylic acid, 2,6-dimethyl-, 2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethyl ester 343-Pyridinecarboxylic acid, 2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethyl ester 351H-pyrrole-3-carboxylic acid, 2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethyl ester 363-Thiophenecarboxylic acid, 2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethyl ester 373-Furancarboxylic acid, 2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethyl ester 381H-indole-7-carboxylic acid, 2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethyl ester 391H-Indene-7-carboxylic acid, 2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethyl ester 408-Quinolinecarboxylic acid, 2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethyl ester 41Quinoline-3-carboxylic acid, 2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethyl ester 42Benzo[b]thiophene-3-carboxylic acid, 2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethyl ester 431H-Indole-3-carboxylic acid, 2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethyl ester 44Benzofuran-3-carboxylic acid, 2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethyl ester 45Benzofuran-2-carboxylic acid, 2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethyl ester 462-Thiophenecarboxylic acid, 2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethyl ester 472-Furancarboxylic acid, 2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethyl ester 481H-Pyrrole-2-carboxylic acid, 2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethyl ester 49Tetrahydro-2H-pyran-4-carboxylic acid, 2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethyl ester 504-Methylpiperazine-1-carboxylic acid, 2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethyl ester 51Morpholine-4-carboxylic acid, 2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethyl ester 522-Pyridinecarboxylic acid, 2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethyl ester

The present invention also provides pharmaceutical compositionscomprising a compound of the present invention, either as such or aspharmaceutically acceptable salt, and one or more pharmaceuticallyacceptable carriers and/or excipients.

The compounds of the present invention may be administered as the soleactive agent or in combination with one or more other pharmaceuticalactive ingredients including those currently used in the treatment ofrespiratory disorders, e.g. beta2-agonists, antimuscarinic agents,mitogen-activated protein kinases (P38 MAP kinase) inhibitors, nuclearfactor kappa-B kinase subunit beta (IKK2) inhibitors, human neutrophilelastase (FINE) inhibitors, phosphodiesterase 4 (PDE4) inhibitors,leukotriene modulators, non-steroidal anti-inflammatory agents (NSAIDs),antitussive agents, mucus regulators, mucolytics,expectorant/mucokinetic modulators, peptide mucolytics, antibiotics,inhibitors of JAK, SYK inhibitors, inhibitors of PI3 Kdelta or PI3Kgamma, M3-antagonists/beta2-agonists (MABA), andM3-antagonists/PDE4-inhibitors (MAPI).

The present invention also provides combinations of a compound of thepresent invention, either as such or as pharmaceutically acceptablesalt, with a β2-agonist selected from the group consisting ofcarmoterol, GSK-642444, indacaterol, milveterol, arformoterol,arformoterol tartrate, formoterol, formoterol fumarate, salmeterol,salmeterol xinafoate, salbutamol, albuterol, levalbuterol, terbutaline,indacaterol (QAB-149), AZD-3199, BI-1744-CL, LAS-100977, GSK159797,GSK59790, GSK159802, GSK642444, GSK678007, GSK96108, bambuterol,isoproterenol, procaterol, clenbuterol, reproterol, fenoterol,bitolterol, brodxatelor and ASF-1020 and salts thereof.

The present invention also provides combinations of a compound of thepresent invention, either as such or as pharmaceutically acceptablesalt, with an antimuscarinic agent selected from the group consisting ofaclidinium, tiotropium, tiotropium bromide (Spiriva®), ipratropium,ipratropium bromide, trospium, glycopyrrolate, NVA237, LAS34273,GSK656398, GSK233705, GSK57319, LAS35201, QAT370, and oxitropium salts.

The present invention also provides combinations of a compound of thepresent invention, either as such or as pharmaceutically acceptablesalt, with a PDE4 inhibitor selected from the group consisting ofAN-2728, AN-2898, CBS-3595, apremilast, ELB-353, KF-66490, K-34,LAS-37779, IBFB-211913, AWD-12-281, cipamfylline, cilomilast,roflumilast, BAY19-8004 and SCH-351591, AN-6415, indus-82010, TPI-PD3,ELB-353, CC-11050, GSK-256066, oglemilast, OX-914, tetomilast, MEM-1414,and RPL-554.

The present invention also provides combinations of a compound of thepresent invention, either as such or as pharmaceutically acceptablesalt, with a P38 MAP kinase inhibitor selected from the group consistingof semapimod, talmapimod, pirfenidone, PH-797804, GSK-725, GSK856553,GSK681323, minokine, and losmapimod and salts thereof.

In a preferred embodiment, the present invention provides combinationsof a compound of the invention with an IKK2 inhibitor.

The present invention also provides combinations of a compound of thepresent invention with a HNE inhibitor selected from the groupconsisting of AAT, ADC-7828, aeriva, TAPI, AE-3763, KRP-109, AX-9657,POL-6014, AER-002, AGTC-0106, respriva, AZD-9668, zemaira, AAT IV,PGX-100, elafin, SPHD-400, prolastin C and prolastin inhaled.

The present invention also provides combinations of a compound of thepresent invention with a leukotriene modulator selected from the groupconsisting of montelukast, zafirlukast, and pranlukast.

The present invention also provides combinations of a compound of thepresent invention with a NSAID selected from the group consisting ofibuprofen and ketoprofen.

The present invention also provides combinations of a compound of thepresent invention with an antitussive agent, selected from the groupconsisting of codeine and dextramorphan.

The present invention also provides combinations of a compound of thepresent invention with a mucolytic, selected from the group consistingof N acetyl cysteine and fudostein.

The present invention also provides combinations of a compound of thepresent invention with an expectorant/mucokinetic modulator, selectedfrom the group consisting of ambroxol, hypertonic solutions (e.g. salineor mannitol) and surfactant.

The present invention also provides combinations of a compound of thepresent invention with a peptide mucolytic, selected from the groupconsisting of recombinant human deoxyribonuclease I (dornase-alfa andrhDNase) and helicidin.

The present invention also provides combinations of a compound of thepresent invention, with an antibiotic, selected from the groupconsisting of azithromycin, tobramycin, and aztreonam.

The present invention also provides combinations of a compound of thepresent invention with a mucus regulator selected from the groupconsisting of INS-37217, diquafosol, sibenadet, CS-003, talnetant,DNK-333, MSI-1956, and gefitinib.

The present invention also provides combinations of a compound of thepresent invention, either as such or as pharmaceutically acceptablesalt, with an inhibitor of JAK, selected from the group consisting ofCP-690550 and GLPG0634.

The present invention also provides combinations of a compound of thepresent invention, either as such or as pharmaceutically acceptablesalt, with a SYK inhibitor selected from the group consisting of R406,R343, and PRT062607.

The present invention also provides a compound of the present inventionfor use as a medicament.

The present invention also relates to the use of a compound of thepresent invention to decrease the number, activity and movement of theinflammatory cells in vitro and/or in vivo.

The present invention is also directed to compounds of the presentinvention for use in the prevention or treatment of any disease whereinthe decrease in the number, activity and movement of inflammatory cellsis involved.

In a further aspect, the present invention provides the use of compoundsof the present invention for the prevention and/or treatment of anydisease wherein the decrease in the number, activity and movement ofinflammatory cells is involved.

In particular, compounds of the present invention, either alone orcombined with one or more active ingredients, may be administered forthe prevention and/or treatment of a disease of the respiratory tractcharacterized by airway obstruction such as asthma and COPD.

In a further aspect the present invention provides the use of compoundsof the present invention for the preparation of a medicament for theprevention and/or treatment of any disease wherein the decrease in thenumber, activity and movement of inflammatory cells is involved.

Moreover the present invention provides a method for prevention and/ortreatment of any disease wherein the decrease in the number, activityand movement of inflammatory cells is involved, said method comprisingadministering to a patient in need of such treatment a therapeuticallyeffective amount of a compound of the invention.

The present invention also provides pharmaceutical preparations ofcompounds of the present invention suitable for administration byinhalation, by injection, orally or intra-nasally. Inhalablepreparations include inhalable powders, propellant-containing meteringaerosols, and propellant-free inhalable formulations.

The present invention is also directed to a device which may be asingle- or multi-dose dry powder inhaler, a metered dose inhaler or anebulizer, in particular a soft mist nebulizer containing a compound ofthe present invention.

The present invention is also directed to a kit comprising apharmaceutical composition of a compound of the present invention aloneor in combination with or in admixture with one or more pharmaceuticallyacceptable carriers and/or excipients and a device which may be asingle- or multi-dose dry powder inhaler, a metered dose inhaler or anebulizer.

The compounds of the present invention may be prepared according to avariety of synthetic steps which are carried out according toconventional methods and techniques or which are hereinbelow described.

In one aspect, the invention provides processes for the preparation ofcompounds of the present invention and intermediates thereof.

Some of the processes used for the preparation of the compounds offormula (I′), as described in the Scheme below, may also be applied tocompounds of formula (I).

Procedures for the preparation of the compounds of the presentinvention.

According to particular embodiments, the compounds of the invention maybe prepared according to different routes described in the above scheme,depending on the nature of the substituents R₁ and R₂.

In general, the compounds of the present invention may be prepared bythe methods illustrated in the general reaction scheme or bymodification thereof, using readily available starting materials,reagents and conventional synthesis procedures. In these reactions, itis also possible to make use of variants that are well known to theperson skilled in the art.

Compounds of formula (III) may be readily prepared from known compoundsby known methods, starting from compounds of general formula (II) (seeJ. Med. Chem., 1982, 25, 1492-1495, which is incorporated herein byreference in its entirety). They are also commercially available.

The compounds of formula (IV) may be conveniently prepared according tostandard procedures reported in the literature. For instance they may beprepared by treatment of compounds of general formula (III) with a basesuch as potassium acetate. This reaction is usually performed in asuitable polar solvent such as DMF and typically proceeds at atemperature range from 80 to 110° C., over a period of 0.5 to 4 hours.

The compounds of formula (V) may be prepared by hydrolyzing thecompounds of formula (IV). This reaction is preferably carried out bysubjecting compounds (IV) to the action of an enzyme, such asimmobilized Lipase from Candida antarctica (Sigma Aldrich) (seeTetrahedron, 50, 13165-13172, 1994, which is incorporated herein byreference in its entirety).

The compounds of general formula (VII) may be prepared starting from thereaction of a compound of formula (V) with a compound of formula (VI) inthe presence of paraformaldehyde, using known procedures for theisoxazolidine formation, by cycloaddition of nitrones (see J. Med.Chem., 25, 1492-1495, 1982, which is incorporated herein by reference inits entirety). The reaction is conveniently carried out in a protogenicsolvent, such as ethanol, at temperatures ranging from 80 to 100° C.Hydroxyl amines of formula (VI) are either commercially available or maybe easily prepared using known procedures, for example by reducing anoxime with a reducing agent, such as borane pyridine complex (see J.Med. Chem., 40, 1955-1968, 1997, which is incorporated herein byreference in its entirety) or by reaction of O-tetrahydropyranylhydroxylamine with a suitable alkylating agent such as alkyl halides(see Chem. Pharm. Bull., 46, 966-972, 1998, which is incorporated hereinby reference in its entirety).

Conversion of the hydroxyl group of compounds of general formula (VII)into an ester, carbonate, carbamate or thiocarbonate, may be easilyperformed by reacting compounds of general formula (VII) with compoundsof general formula (VIII), (IX), (X), (XI), (XII) or (XIII) followingthe described synthetic route (Routes A through D).

The skilled person may introduce, where appropriate, suitable variationsto the conditions specifically described in the examples in order toadapt the synthetic routes to the provision of further compounds of theinvention. Such variations may include, but are not limited to, use ofappropriate starting materials to generate different compounds, changesin the solvent and temperature of reactions, replacements of a reactantwith analogous chemical role, introduction or removal ofprotection/deprotection stages of functional groups sensitive toreaction conditions and reagents, as well as introduction or removal ofspecific synthetic steps oriented to further fictionalization of thechemical scaffold.

Reaction of the intermediates of general formula (VII) with acylchlorides (VIII), following Route A, to obtain compounds of generalformula (I) is conveniently performed in DCM (dichloromethane) assolvent in the presence of a base such as triethylamine, DIPEA(N,N-diisopropyl-ethylamine) or pyridine at RT over a period of 4 to 50hours.

Alternatively, with Route B, conversion of the hydroxyl group ofcompounds of general formula (VII) into a carbamate may be easilyperformed by reacting compounds of general formula (VII) with compoundsof general formula (IX), following known procedures. The reaction isconveniently performed in DCM as solvent in the presence of a base suchas DMAP, at RT over a period of 4 to 50 hours.

Following using Route C, reaction of the intermediates of generalformula (VII) with CDI (1,1′-Carbonyldiimidazole) followed by additionof desired alcohol (X) or thiol (XI) or amine (XII) to obtain compoundsof general formula (I) is conveniently performed in THF(tetrahydrofuran) at RT over a period of 4 to 50 hours.

Alternatively, according to Route D, conversion of the hydroxyl group ofcompounds of general formula (VII) into compounds of general formula (I)can be achieved by reacting compounds of general formula (XIII) withHOBt (hydroxybenzotriazole) followed by adding of compounds of generalformula (VII), EDC (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide) andDMAP (4-dimethylaminopyridine). The reaction is conveniently performedin DMF as solvent at RT over a period of 4 to 50 hours.

From all of the above, it should be clear to the skilled person that anyof the described groups may be present as such or in any properlyprotected form. In particular, functional groups present in theintermediate and compounds and which could generate unwanted sidereaction and by-products, need to be properly protected before thealkylation, acylation, coupling or sulfonylation takes place. Likewise,subsequent deprotection of those same protected groups may follow uponcompletion of the said reactions.

In the present invention, unless otherwise indicated, the term“protecting group” designates the protective groups which were adaptedto preserve the function of the group it is bound to. Typically,protective groups are used to preserve amino, hydroxyl, or carboxylfunctions. Appropriate protecting groups may thus include, for example,benzyl, benzyloxycarbonyl, t-butoxycarbonyl, alkyl or benzyl esters orthe like, which are well known to those skilled in the art (see, for ageneral reference, 20 T. W. Green; Protective Groups in OrganicSynthesis (Wiley, N.Y. 1981), which is incorporated herein by referencein its entirety).

From all of the above, it is clear to the person skilled in the art thatby selecting the starting material with a proper stereochemicalconfiguration, any of the possible stereoisomers of formula (I) can beobtained.

Advantageously, the compounds of the present invention may beadministered for example, at a dosage of from 0.001 to 1000 mg/day,preferably from 0.1 to 500 mg/day.

When they are administered by the inhalation route, the dosage of thecompounds of the present invention is advantageously from 0.01 to 20mg/day, preferably from 0.1 to 10 mg/day.

Preferably, the compounds of the present invention alone or combinedwith one or more other active ingredients may be administered for theprevention and/or treatment of any obstructive respiratory disease suchas asthma, chronic bronchitis, and chronic obstructive pulmonary disease(COPD).

However the compounds of the present invention may be administered forthe prevention and/or treatment of any disease wherein the decrease inthe number, activity and movement of inflammatory cells is involved.

Examples of such diseases include: diseases involving inflammation suchas asthma and other allergic disorders, COPD, acute rhinitis; reverseacute transplant rejection and acute exacerbations of selectedautoimmune disorders, graft-versus-host disease in bone-marrowtransplantation; autoimmune disorders such as rheumatoid and otherarthritis; skin conditions such as systemic lupus erythematosus,systemic dermatomyositis, psoriasis; inflammatory bowel disease,inflammatory ophthalmic diseases, autoimmune hematologic disorders, andacute exacerbations of multiple sclerosis; kidney, liver, heart, andother organ transplantation; Beh

et's acute ocular syndrome, endogenous uveitis, atopic dermatitis,inflammatory bowel disease, and nephrotic syndrome; Hodgkin's diseaseand non-Hodgkin's lymphoma, multiple myeloma and chronic lymphocyticleukemia (CLL); autoimmune hemolytic anemia and thrombocytopeniaassociated with CLL, leukemia, and malignant lymphoma.

Preferably the compounds of the invention may be administered for theprevention and/or treatment of respiratory diseases such as from mild toacute severe conditions of asthma and COPD.

Other features of the invention will become apparent in the course ofthe following descriptions of exemplary embodiments which are given forillustration of the invention and are not intended to be limitingthereof.

EXAMPLES

In the reported experimental procedures, the following abbreviations maybe used:

-   TEA=triethylamine;-   DCM=dichloromethane;-   RT=room temperature;-   AcOEt=ethyl acetate;-   DMF=N,N-dimethylformamide;-   DMSO dimethylsulfoxide;-   HATU=O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate;-   DMAP=4-dimethylaminopyridine; and-   DIPEA=ethyldiisopropylamine.

Example 1 Preparation of isobutyric acid2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4-b,12-difluoro-5-hydroxy-4-a,6a-dimethyl-2-oxo-2,4-a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethylester (compound 1)

To a stirred solution of intermediate 2 (600 mg, 1.124 mmol) and DIPEA(0.391 ml, 2.247 mmol) in dry dichloromethane (30 ml), under nitrogenatmosphere at 5° C., isobutyryl chloride (0.235 ml, 2.247 mmol) wasadded, and the reaction mixture was stirred at 5° C. for 10 minutes andat RT for 16 hours. DIPEA (0.196 ml, 1.124 mmol) and isobutyryl chloride(0.118 ml, 1.124 mmol) were further added, and the mixture was stirredat RT for 72 hours. Another portion of DIPEA (0.196 ml, 1.124 mmol) andisobutyryl chloride (0.118 ml, 1.124 mmol) were further added, and thereaction mixture was stirred at RT for 1 hour and at 50° C. for 1.5hours. The reaction mixture was diluted with DCM (100 ml), and theorganic layer was washed with 1N HCl, a saturated solution of NaHCO₃ andbrine, dried (Na₂SO₄) and concentrated. The crude was purified by silicagel flash chromatography in gradient elution from DCM/AcOEt 98:2 toDCM/AcOEt 92:8, to afford 481 mg of pure compound (71% yield; Rf=0.37 inAcOEt/DCM 10:90).

¹H NMR (300 MHz, DMSO-d₆) ppm 7.31-7.45 (m, 2 H), 7.26 (dd, 1 H),6.98-7.10 (m, 2 H), 6.29 (dd, 1 H), 6.08 (s, 1 H), 5.62 (d, 1 H),5.42-5.78 (m, 1 H), 5.06 (d, 1 H), 4.90 (d, 1 H), 4.18-4.32 (m, 1 H),4.17 (t, 1 H), 3.44-3.62 (m, 1 H), 2.56-2.71 (m, 2 H), 2.63 (spt, 1 H),2.04-2.34 (m, 3 H), 1.84-1.96 (m, 1 H), 1.63-1.83 (m, 1 H), 1.52-1.63(m, 2 H), 1.50 (s, 3 H), 1.14 (d, 3 H), 1.13 (d, 3 H), 0.94 (s, 3 H)

LC-MS (ESI POS): 604.10 MH+

[α]_(D) ²⁵=+58.3 (c 0.2; MeOH)

The compounds listed in Table were prepared as previously described forcompound 1, by acylation of intermediate 2 with suitable acyl chlorides.

TABLE 1 Com- pound Structure Yield Analytical 3

61% LC-MS (ESI POS): 590.14 MH+ [α]_(D) ²⁵ = +59.7 (c 0.2 MeOH) ¹H NMR(300 MHz, DMSO-d₆) ppm 7.31-7.43 (m, 2 H), 7.26 (dd, 1 H), 6.90- 7.10(m, 2 H), 6.29 (dd, 1 H), 6.08 (s, 1 H), 5.62 (dd, 0 H), 5.45-5.73 (m, 1H), 5.06 (d, 1 H), 4.90 (d, 1 H), 4.19-4.31 (m, 1 H), 4.17 (t, 1 H),3.45-3.64 (m, 1 H), 2.56-2.69 (m, 2 H), 2.41 (q, 2 H), 2.07-2.28 (m, 3H), 1.82-1.93 (m, 1 H), 1.64-1.81 (m, 1 H), 1.51-1.64 (m, 3 H), 1.50 (s,3 H), 1.07 (t, 3 H), 0.94 (s, 3 H) 4

70% LC-MS (ESI POS): 772.6 MH+ [α]_(D) ²⁵ = +65.9 (c 0.2 CHCl₃) ¹H NMR(300 MHz, DMSO-d₆) ppm 7.31-7.41 (m, 2 H), 7.26 (d, 1 H), 6.98- 7.10 (m,2 H), 6.29 (dd, 1 H), 6.08 (s, 1 H), 5.62 (d, 1 H), 5.43-5.79 (m, 1 H),5.06 (d, 1 H), 4.89 (d, 1 H), 4.18-4.29 (m, 1 H), 4.17 (t, 1 H),3.45-3.61 (m, 1 H), 2.55-2.73 (m, 2 H), 2.37 (t, 2 H), 2.03-2.31 (m, 3H), 1.88 (d, 1 H), 1.62- 1.81 (m, 1 H), 1.51-1.62 (m, 4 H), 1.50 (s, 3H), 1.24 (s, 24 H), 0.93 (s, 3 H), 0.86 (t, 3 H) 5

LC-MS (ESI POS): 798.31 MH+ [α]_(D) ²⁵ = +47 (c 0.0765; MeOH) 1H NMR(300 MHz, DMSO-d6) ppm 7.30-7.39 (m, 2 H), 7.26 (dd, 1 H), 6.97- 7.09(m, 2 H), 6.29 (dd, 1 H), 6.08 (s, 1 H), 5.62 (d, 1 H), 5.47-5.81 (m, 1H), 5.21-5.40 (m, 2 H), 5.06 (d, 1 H), 4.88 (d, 1 H), 4.07-4.31 (m, 2H), 3.52 (q, 1 H), 2.60 (dd, 2 H), 2.37 (t, 2 H), 2.06- 2.26 (m, 3 H),1.92-2.05 (m, 4 H), 1.87 (d, 1 H), 1.62-1.80 (m, 1 H), 1.50 (s, 3 H),1.45-1.61 (m, 4 H), 1.26 (m, 20 H), 0.93 (s, 3 H), 0.85 (t, 3 H) 6

56% LC-MS (ESI POS): 618.23 MH+ [α]_(D) ²⁵ = +68.6 (c 0.2 CHCl₃) ¹H NMR(300 MHz, DMSO-d₆) ppm 7.30-7.42 (m, 2 H), 7.26 (dd, 1 H), 6.93- 7.14(m,2 H), 6.29 (dd, 1 H) , 6.08 (s, 1 H), 5.62 (d, 1 H), 5.42-5.79 (m, 1 H),5.07 (d, 1 H), 4.89 (d, 1 H), 4.23 (m, 1 H), 4.17 (t, 1 H), 3.43-3.63(m, 1 H), 2.55-2.66 (m, 2 H), 2.39 (t, 2 H), 2.00- 2.25 (m, 3 H), 1.88(d, 1 H), 1.63-1.81 (m, 1 H), 1.42-1.61 (m, 4 H), 1.50 (s, 3 H),1.26-1.41 (m, 2 H), 0.93 (s, 3 H), 0.81-0.92 (m, 3 H) 7

47% LC-MS (ESI POS): 576.23 MH+ [α]_(D) ²⁵ = +53.8 (c 0.2 MeOH) ¹H NMR(300 MHz, DMSO-d₆) ppm 7.30-7.40 (m, 2 H), 7.26 (dd, 1 H), 6.88- 7.12(m, 2 H), 6.29 (dd, 1 H), 6.08 (s, 1 H), 5.62 (dd, 1 H), 5.39-5.77 (m, 1H), 5.05 (d, 1 H), 4.88 (d, 1 H), 4.18-4.28 (m, 1 H), 4.17 (t, 1 H),3.46-3.67 (m, 1 H), 2.58-2.71 (m, 1 H), 2.60 (dd, 1 H), 2.12-2.32 (m, 3H), 2.10 (s, 3 H), 1.81- 1.94 (m, 1 H), 1.64-1.81 (m, 1 H), 1.51- 1.64(m, 2 H), 1.50 (s, 3 H), 0.93 (s, 3 H) 8

29% LC-MS (ESI POS): 638.15 MH+ [α]_(D) ²⁵ = +66 (c 0.2 MeOH) ¹H NMR(300 MHz, DMSO-d₆) ppm 7.93-8.06 (m, 2 H), 7.66-7.76 (m, 1 H), 7.49-7.63(m, 2 H), 7.33-7.42 (m, 2 H), 7.28 (dd, 1 H), 7.00-7.15 (m, 2 H), 6.30(dd, 1 H), 6.09 (s, 1 H), 5.67 (dd, 1 H), 5.49-5.85 (m, 1 H), 5.35 (d, 1H), 5.17 (d, 1 H), 4.23-4.32 (m, 1 H), 4.21 (t, 1 H), 3.47-3.65 (m, 1H), 2.56- 2.69 (m, 2 H), 2.09-2.32 (m, 3 H), 1.91-2.04 (m, 1 H),1.66-1.83 (m, 1 H), 1.53-1.65 (m, 2 H), 1.51 (s, 3 H), 1.00 (s, 3 H) 9

54% LC-MS (ESI POS): 592.13 MH+ [α]_(D) ²⁵ = +48.6 (c 0.2 MeOH) ¹H NMR(300 MHz, DMSO-d₆) ppm 7.30-7.39 (m, 2 H), 7.26 (dd, 1 H), 6.96- 7.10(m, 2 H), 6.29 (dd, 1 H), 6.08 (s, 1 H), 5.63 (dd, 1 H), 5.47-5.75 (m, 1H), 5.07 (d, 1 H), 4.94 (d, 1 H), 4.19-4.29 (m, 1 H), 4.18 (t, 1 H),3.74 (s, 3 H), 3.45-3.61 (m, 1 H), 2.62-2.72 (m, 1 H), 2.61 (dd, 1 H),2.04-2.29 (m, 3 H), 1.85 (d, 1 H), 1.63-1.80 (m, 1 H), 1.51-1.63 (m, 2H), 1.50 (s, 3 H), 0.95 (s, 3 H) 10

66% LC-MS (ESI POS): 608.08 MH+ [α]_(D) ²⁵ = +50.8 (c 0.2 MeOH) ¹H NMR(300 MHz, DMSO-d₆) ppm 7.30-7.42 (m, 2 H), 7.26 (d, 1 H), 6.94- 7.10 (m,2 H), 6.29 (dd, 1 H), 6.08 (s, 1 H), 5.63 (dd, 1 H), 5.45-5.78 (m, 1 H),5.22 (d, 1 H), 5.06 (d, 1 H), 4.19-4.27 (m, 1 H), 4.18 (m, 1 H),3.44-3.62 (m, 1 H), 2.59-2.72 (m, 1 H), 2.61 (dd, 1 H), 2.34 (s, 3 H),2.02-2.29 (m, 3 H), 1.80- 1.89 (m, 1 H), 1.64-1.79 (m, 1 H), 1.51- 1.62(m, 2 H), 1.50 (s, 3 H), 0.94 (s, 3 H) 11

54% LC-MS (ESI POS): 618.13 MH+ [α]_(D) ²⁵ = +63.4 (c 0.2 MeOH) ¹H NMR(300 MHz, DMSO-d₆) ppm 7.29-7.46 (m, 2 H), 7.26 (dd, 1 H), 6.94- 7.13(m, 2 H), 6.29 (dd, 1 H), 6.08 (s, 1 H), 5.62 (dd, 1 H), 5.39-5.81 (m, 1H), 5.08 (d, 1 H), 4.89 (d, 1 H), 4.21-4.39 (m, 1 H), 4.17 (t, 1 H),3.41-3.63 (m, 1 H), 2.56-2.70 (m, 2 H), 2.27 (d, 2 H), 2.07-2.25 (m, 3H), 1.94-2.09 (m, 1 H), 1.80-1.94 (m, 1 H), 1.64-1.80 (m, 1 H),1.51-1.62 (m, 2 H), 1.50 (s, 3 H), 0.94 (s, 3 H), 0.95 (d, 6 H) 12

33% LC-MS (ESI POS): 618.12 MH+ [α]_(D) ²⁵ = +53.6 (c 0.2 MeOH) ¹H NMR(300 MHz, DMSO-d₆) ppm 7.30-7.41 (m, 2 H), 7.26 (dd, 1 H), 6.95-7.12 (m,2 H), 6.29 (dd, 1 H), 6.08 (s, 1 H), 5.61 (d, 1 H), 5.48-5.75 (m, 1 H),5.06 (d, 1 H), 4.91 (d, 1 H), 4.17 (t, 1 H), 4.09-4.35 (m, 1 H), 3.53(q, 1 H), 2.56-2.68 (m, 2 H), 2.04-2.26 (m, 3 H), 1.89 (d, 1 H),1.62-1.80 (m, 1 H), 1.50 (s, 3 H), 1.57 (d, 2 H), 1.19 (s, 9 H), 0.94(s, 3 H) 13

79% LC-MS (ESI POS): 652.14 MH+ [α]_(D) ²⁵ = +129.6 (c 0.3; DCM) ¹H NMR(300 MHz, DMSO-d₆) ppm 7.13-7.46 (m, 8 H), 6.76-7.13 (m, 2 H), 6.28 (dd,1 H), 6.08 (s, 1 H), 5.60 (d, 1 H), 5.40-5.77 (m, 1 H), 5.10 (d, 1 H),4.93 (d, 1 H), 4.11-4.31 (m, 2 H), 3.78 (s, 2 H), 3.43-3.66 (m, 1 H),2.55- 2.66 (m, 2 H), 2.09-2.30 (m, 3 H), 1.86 (d, 1 H), 1.72 (d, 1 H),1.49 (s, 3 H), 1.33-1.63 (m, 2 H), 0.93 (s, 3 H) 14

60% LC-MS (ESI POS): 628.2 MH+ [α]_(D) ²⁵ = +34.9 (c 0.2, MeOH) ¹H NMR(300 MHz, DMSO-d₆) ppm 8.02 (dd, 1 H), 7.32-7.43 (m, 3 H), 7.27 (d, 1H), 6.98-7.13 (m, 2 H), 6.73 (dd, 1 H), 6.30 (dd, 1 H), 6.09 (s, 1 H),5.66 (d, 1 H), 5.46-5.79 (m, 1 H), 5.30 (d, 1 H), 5.11 (d, 1 H), 4.20(t, 1 H), 4.09- 4.36 (m, 1 H), 3.47-3.66 (m, 1 H), 2.63 (dd, 2 H),2.06-2.27 (m, 3 H), 1.93 (d, 1 H), 1.64-1.83 (m, 1 H), 1.56 (dd, 2 H),1.51 (s, 3 H), 0.97 (s, 3 H)

Example 2 Preparation of Cyclopentanecarboxylic acid2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethylester (compound 15)

Cyclopentanecarboxylic acid (137 mg, 1.2 mmol, 1.2 eq) was dissolved inDMF (5 ml), 1-hydroxybenzotriazole hydrate (162 mg, 1.2 mmol, 1.2 eq)was added, and the reaction mixture was stirred 20 minutes. Intermediate2 (534 mg, 1 mmol), 4-(dimethylamino)pyridine (305 mg, 2.5 mmol, 2.5eq), and EDC*HCl (230 mg, 1.2 mmol, 1.2 eq) were added in this order,and the reaction mixture was stirred at RT overnight. The conversion wasmonitored by TLC analysis (Hex/EtOAc 7/6). The reaction was quenchedwith HCl 0.6N and the product extracted with EtOAc twice. The collectedorganic phases were washed with NaHCO₃ saturated solution, brine anddried over anhydrous Na₂SO₄. The crude was purified treating with NaOH1N (10 ml), pyridine (used to transfer cylopentanecarboxylic acid in theaqueous layer, 2 ml), and EtOAc (30 ml). The organic layer was washedtwice with water and filtered on a silica pad. Compound 15 was obtainedas a solid that was dried under vacuum at 50° C. for 2 hours (300 mg,yield 47.6%).

LC-MS (ESI POS): 630.10 MH+

¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.34 (d, J=8.82 Hz, 2 H), 7.19-7.28 (m,1 H), 7.04 (d, J=8.82 Hz, 2 H), 6.18-6.37 (m, 1 H), 5.97-6.13 (m, 1 H),5.46-5.75 (m, 2 H), 4.78-5.17 (m, 2 H), 4.06-4.31 (m, 2 H), 3.42-3.55(m, 1 H), 2.78-2.93 (m, 1 H), 2.54-2.74 (m, 2 H), 2.09 (m, 3 H), 1.49(m, 15 H), 0.93 (s, 3 H).

The compounds listed in Table 2 were prepared as previously described.

TABLE 2 Compound Structure Yield Analytical 16

71% LC-MS (ESI POS): 602.2 MH+ ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.26-7.37(m, 2 H), 7.14-7.24 (m, 1 H), 6.90-7.05 (m, 2 H), 6.15-6.40 (m, 1 H),5.99-6.06 (m, 1 H), 5.39-5.72 (m, 2 H), 4.74-5.12 (m, 2 H), 4.03-4.22(m, 2 H), 3.39-3.57 (m, 1 H), 2.50-2.70 (m, 2 H), 1.94-2.22 (m, 3 H),1.76-1.90 (m, 1 H), 1.59-1.73 (m, 2 H), 1.36-1.56 (m, 5 H), 0.71-1.01(m, 7 H). 17

46% LC-MS (ESI POS): 639.2 MH+ ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.76-8.95(m, 2 H), 7.76-7.88 (m, 2 H), 7.37 (d, J = 8.82 Hz, 2 H), 7.23-7.31 (m,1 H), 7.09 (d, J = 8.82 Hz, 2 H), 6.24-6.35 (m, 1 H), 6.09 (s, 1 H),5.51-5.76 (m, 2 H), 5.11-5.45 (m, 2 H), 4.09- 4.32 (m, 2 H), 3.48-3.65(m, 1 H), 2.59-2.75 (m, 2 H), 2.12-2.36 (m, 3 H), 1.89-2.06 (m, 1 H),1.51 (m, 6 H), 0.98 (s, 3 H).

Example 3 Preparation of Isobutyl methyl carbonate2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethylester (compound 18)

Intermediate 2 (350 mg, 0.66 mmol) in THF (3 ml) was added at RT withCDI (127 mg, 0.79 mmol, 1.2 eq) at portions. The reaction mixture wasstirred 1 hour; conversion was detected by TLC analysis (EtOAc 100%). Tothe reaction mixture was added isobutyl alcohol (1.0 ml, 10 mmol) at 0°C. and stirred 1 hour at RT. Traces of the desired product wereobserved. The reaction mixture was then heated to 50° C. for four hours;conversion increase. After 12 hours at 50° C. complete conversion wasdetected by TLC analysis (hexane/EtOAc 3/7). The solvent was evaporatedunder vacuum and the crude treated with EtOAc/H₂O. The organic layerscollected were dried over anhydrous Na₂SO₄, the crude was purified on asilica pad to yield compound 18 (240 mg, yield 58%).

LC-MS (ESI POS): 634.2 LC-MS

¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.34 (d, J=8.82 Hz, 2 H), 7.20-7.30 (m,1 H), 7.04 (d, J=8.82 Hz, 2 H), 6.21-6.37 (m, 1 H), 6.00-6.12 (m, 1 H),5.47-5.72 (m, 2 H), 4.83-5.17 (m, 2 H), 4.10-4.29 (m, 2 H), 3.91 (dd,J=6.62, 0.88 Hz, 2 H), 3.43-3.60 (m, 1 H), 2.55-2.74 (m, 2 H), 2.04-2.29(m, 3 H), 1.81-1.99 (m, 2 H), 1.64-1.76 (m, 1 H), 1.49 (m, 5 H),0.81-0.96 (m, 9 H).

Compound 19 was prepared as previously described for compound 18starting from hexyl alcohol.

Compound Structure Yield Analytical 19

30% LC-MS (ESI POS): 662.2 MH+ ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.33 (s,2 H), 7.18-7.29 (m, 1 H), 7.00-7.11 (m, 2 H), 6.22-6.37 (m, 1 H),6.02-6.11 (m, 1 H), 5.49-5.77 (m, 2 H), 4.79-5.17 (m, 2 H), 4.14-4.27(m, 2 H), 4.04-4.13 (m, 2 H), 3.44-3.62 (m, 1 H), 2.53-2.68 (m, 2 H),2.03-2.29 (m, 3 H), 1.77-1.90 (m, 1 H), 1.49 (m, 8 H), 1.22-1.36 (m, 6H), 0.76-0.99 (m, 6 H).

Example 4 Preparation ofDimethylcarbamate2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethylester (compound 20)

Intermediate 2 (310 mg, 0.58 mmol) in CH₂Cl₂ (3 ml) was added at RT withCDI (111 mg, 0.70 mmol, 1.2 eq) at portions. The reaction mixture wasstirred 1 hour; complete conversion was detected by TLC analysis (EtOAc100%). CH₂Cl₂ was evaporated under vacuum and the crude was dissolved inTHF (2 ml) and then was added with 2 M dimethylamine solution in THF at0° C. (1.15 ml, 2.32 mmol) and stirred 1 hour at RT. Complete conversionwas detected by TLC analysis (hexane/EtOAc 2/8). The solvent wasevaporated under vacuum and the crude treated with CH₂Cl₂/H₂O. Theorganic layers collected were dried over anhydrous Na₂SO₄, the crude waspurified on a silica pad, then the obtained beige solid was trituratedin a hexane/ethyl acetate mixture (8/2, 8 ml) for one night. The solidfiltered was dried under vacuum at 50° C. till constant weight, yieldingcompound 20 (200 mg, yield 57%)

LC-MS (ESI POS): 605.2 LC-MS

¹H NMR (400 MHz, DMSO-d₆) δppm 7.31-7.44 (m, 2 H), 7.21-7.30 (m, 1 H),6.99-7.07 (m, 2 H), 6.20-6.43 (m, 1 H), 6.01-6.12 (m, 1 H), 5.47-5.76(m, 2 H), 4.69-5.10 (m, 2 H), 4.08-4.25 (m, 2 H), 3.43-3.59 (m, 1 H),2.80-3.00 (m, 6 H), 2.55-2.72 (m, 2 H), 2.03-2.28 (m, 3 H), 1.83-1.96(m, 1 H), 1.65-1.81 (m, 1 H), 1.49 (m, 5 H), 0.93 (s, 3 H).

Compound 21 was prepared as previously described for compound 20starting from methylamine.

Compound Structure Yield Analytical 21

56.3% LC-MS (ESI POS): 591.1 MH+ ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.34(d, J = 8.82 Hz, 2 H), 7.15-7.28 (m, 2 H), 7.03 (d, J = 8.82 Hz, 2 H),6.19-6.41 (m, 1 H), 6.02-6.12 (m, 1 H), 5.45-5.75 (m, 2 H), 4.62-5.07(m, 2 H), 4.12- 4.28 (m, 2 H), 3.40-3.56 (m, 1 H), 2.58 (m, 5 H),2.05-2.34 (m, 3 H), 1.84-1.96 (m, 1 H), 1.56-1.77 (m, 1 H), 1.49 (s, 5H), 0.93 (s, 3 H).

Example 5 Preparation of piperazine-1-carboxylic acid2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethylester (compound 22)

Intermediate 2 (500 mg, 0.94 mmol) in THF (3.5 ml) was added at RT withCDI (180 mg, 1.12 mmol, 1.2 eq) at portions. The reaction mixture wasstirred 1 hour; complete conversion to activated intermediate wasdetected by TLC analysis (Hexane:EtOAc 3/7). The reaction mixture wascooled to 10° C. and then was added with tert-butylpiperazine-1-carboxylate (174 mg, 0.94 mmol, 1.0 eq) and stirred at RTovernight. Conversion was detected by TLC analysis (hexane/EtOAc 3/7).The solvent was evaporated under vacuum and the crude treated withEtOAc/H₂O. The organic layers collected were dried over anhydrous Na₂SO₄and the crude compound intermediate 3 was used in the next step withoutfurther purification (260 mg, yield 37%). A solution of intermediate 3(260 mg, 0.35 mmol) in CH₂Cl₂ (5 ml) was cooled to 0° C. and addeddropwise with trimethyl-silyl trifluoromethanesulfonate (63 μl, 1.0eq,). The reaction mixture was stirred 1 hour at 0° C. and then quenchedwith demineralised water. The organic layer was washed with NaHCO₃saturated solution and then with demineralised water, dried overanhydrous Na₂SO₄ yielding raw compound, that was purified by columnchromatography over silica gel (eluting with EtOAc/TEA 99:1) and driedunder vacuum at 50° C. till constant weight to give compound compound 22(190 mg, 84% yield)

LC-MS (ESI POS): 646.4 MH+

¹H NMR (400 MHz, DMSO-d₆) 8 ppm 7.33 (d, J=8.82 Hz, 3 H), 7.03 (d,J=8.82 Hz, 2 H), 6.19-6.39 (m, 1 H), 6.07 (s, 1 H), 5.46-5.76 (m, 2 H),4.76-5.14 (m, 2 H), 4.05-4.28 (m, 2 H), 3.41-3.60 (m, 1 H), 3.18-3.30(m, 5 H), 2.66 (m, 6 H), 1.95-2.28 (m, 3 H), 1.81-1.95 (m, 1 H),1.57-1.79 (m, 1 H), 1.48 (m, 5 H), 0.93 (s, 3 H).

The compounds listed in the following Table were prepared as previouslydescribed for compound 22 starting from the corresponding intermediate.

Compound Structure Yield Analytical 23

26% LC-MS (ESI POS): 649.4 MH+ ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.17-7.40(m, 3 H), 6.88- 7.11 (m, 2 H), 6.21-6.34 (m, 1 H), 5.99-6.13 (m, 1 H),5.44-5.74 (m, 2 H), 4.99-5.23 (m, 3 H), 4.04-4.34 (m, 2 H), 3.39-3.64(m, 1 H), 3.06-3.25 (m, 3 H), 2.81-2.92 (m, 1 H), 2.70-2.79 (m, 1 H),2.54-2.66 (m, 2 H), 2.03-2.29 (m, 3 H), 1.80-1.92 (m, 1 H), 1.64- 1.78(m, 1 H), 1.49 (m, 5 H), 0.93 (s, 3 H) 24

27% LC-MS (ESI POS): 631.2 MH+ ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.34 (m,3 H), 7.04 (d, J = 8.82 Hz, 2 H), 6.22-6.41 (m, 1 H), 6.08 (s, 1 H),5.41-5.78 (m, 2 H), 4.74-5.18 (m, 2 H), 4.08-4.26 (m, 2 H), 3.69-3.84(m, 1 H), 3.42- 3.59 (m, 1 H), 2.71-2.96 (m, 2 H), 2.54-2.69 (m, 2 H),1.96-2.25 (m, 5 H), 1.80-1.93 (m, 2 H), 1.60-1.75 (m, 3 H), 1.49 (m, 5H), 0.93 (s, 3 H) 25

31% LC-MS (ESI POS): 645.3 MH+ ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.34 (d,J = 8.82 Hz, 3 H), 7.04 (d, J = 8.82 Hz, 2 H), 6.21-6.42 (m, 1 H), 6.08(s, 1 H), 5.42- 5.86 (m, 2 H), 4.80-5.12 (m, 2 H), 4.01-4.30 (m, 2 H),3.41-3.58 (m, 1 H), 2.81-2.97 (m, 2 H), 2.52-2.74 (m, 2 H), 2.31-2.47(m, 2 H), 1.90-2.27 (m, 6 H), 1.63-1.78 (m, 3 H), 1.49 (m, 7 H), 0.93(s, 3 H) Legend * NMR s = singlet d = doublet t = triplet q = quartet dd= doublet of doublets m = multiplet br = broad ESI-POS = electrospraypositive ionization LC-MS = liquid chromatography-mass spectrometryPharmacological Activity of the Compounds of the Present InventionIn vivo Studies.

Example 6 Lipopolysaccharide (LPS)-induced Lung Neutrophilia

The potency and duration of action of the compounds described in thepresent invention were evaluated in vivo in an acute model of lunginflammation following a method described in Am. J. Respir. Crit. CareMed., vol. 162, pp. 1455-1461 (2000), which is incorporated herein byreference in its entierty, with minor modifications. The tests wereperformed on Sprague-Dawley male rats (200 g). Intratrachealinstillation of LPS resulted in a statistically significant increase inneutrophil concentration in BALF, a hallmark of acute ongoing pulmonaryinflammation.

For the dose of glucocorticoid producing a 75% inhibition (ED75 dose)assessment test, compounds (0.01-1 μmoles/Kg of body weight) wereadministered intratracheally as suspension (0.2% Tween 80 in NaCl 0.9%)1 hour before LPS challenge. A dose-response curve of the inhibitoryeffect of the test compounds on LPS-induced lung neutrophilia wasperformed and the ED50 dose of glucocorticoid was taken as a measure ofpotency in this bioassay. The ED50 dose values for some representativecompounds of the present invention were comprised between 0.05 and 0.16μmoles/Kg of body weight.

In a second series of experiments, aimed at the evaluation of theduration of action, the compounds were administered as suspensionintratracheally, at the ED75 dose, administered 24 h before LPSchallenge. The most interesting compounds were active (percent ofinhibition higher than 50%) when administered 24 hours before LPSchallenge.

In vitro Studies.

Example 7 Glucocorticoid Receptor (GR) Translocation Assay Protocol

A quantitative measurement of GR nuclear translocation of the compoundsof the present invention was performed according to ASSAY Drug Devel.Technol., 4(3), pp. 263-272 (2006), which is incorporated herein byreference in its entirety, through a novel cell-based GR-translocationassay in Enzyme Fragment Complementation (EFC) format developed byDiscoveRx (Fremont, Calif.). In the absence of the glucocorticoid, theglucocorticoid receptor (GR) resides in the cytosol complexed with avariety of proteins including heat shock proteins. When a glucocorticoiddiffuses through the cell membrane into the cytoplasm and binds to theglucocorticoid receptor (GR), it results in release of the heat shockproteins and the translocation into the nucleus where it modulates genetranscription.

The DiscoveRx assay uses EFC of b-galactosidase (b-gal) as an indicatorof GR-translocation in engineered CHO-K1 biosensor cells. The enzymeacceptor (EA) fragment of b-gal resides in the nucleus, as designedthrough the use of a proprietary set of sequence additions andmodifications. The small peptide enzyme donor (ED) fragment of b-gal wasfused directly to the C-terminus of GR, and was localized in thecytoplasm in the absence of receptor signaling. Upon binding to a GRligand, the complex translocates to the nucleus, where intact enzymeactivity was restored by complementation and b-gal activity wasdetected.

CHO-K1 cells stably expressing NLS-enzyme acceptor fragment (EA) ofb-gal and GR-enzyme donor (ED) fragment of b-gal were maintained in F12medium (Invitrogen, Carlsbad, Calif.) at 37° C. under a humidifiedatmosphere containing 5% CO₂ and 95% air. The medium contained 10% FBS,2 mM L-glutamine, 50 U/ml penicillin 50 μg/ml streptomycin, and 250μg/ml hygromycin and 500 μg/ml G418 (Invitrogen). GR-translocation wasmeasured using the PathHunter Detection Kit containing cell membranepermeabilizing reagent and beta-gal substrate (DiscoveRx, Fremont,Calif.). All compounds were screened using varying concentrationsranging from 10⁻¹¹ to 10⁻⁶ M. The assay was performed in 48-wells (105cells/well). Incubation with screened compounds was performed at 37° C.for two hours. Detection was made by adding the detection buffer fromthe kit supplied by DiscoveRx and incubating at RT for one hour.Luminescence was detected by using a CENTRO LB 960 microplate reader(Berthold Technologies). Statistical analysis and determinations ofEC50s were performed by using Prism-version 3.0 Graphpad Software (SanDiego, Calif.). Some representative compounds of the invention assayedwith the GR translocation displayed a EC50 comprised between 3.2 nM and207 nM.

Example 8 Inhibition of LPS-Induced Nitric Oxide Production in RAW 264.7Macrophages

An in vitro model based on macrophagic murine cell line RAW 264.7 wasused for testing the anti-inflammatory effects of the corticosteroids ofthe present invention. During the inflammatory process, large amounts ofnitric oxide (NO) were generated by the inducible isoforms of NOsynthase (iNOS). Bacterial lipopolysaccharide (LPS) was commonly used inexperimental settings to stimulate inflammatory responses inmacrophages.

Cells were grown in a culture medium (RPMI supplemented withheat-inactivated 10% fetal calf serum, 2 mM glutamine, 100 U/mlpenicillin and 0.1 mg/ml streptomycin) without phenol red. Cellstimulation was elicited by incubating cells for 24 hours with LPS tofinal concentrations ranging from 100 ng/ml. Treatments with thecompounds of the invention were carried out by adding such compoundsvehicled in DMSO (0.1% final concentration) to the final desiredconcentrations 15 minutes before LPS exposure. As an index of nitricoxide production, the concentration of nitrite was measured in theconditioned media by using the Griess colorimetric reaction (see J.Neuroimmunol., vol. 150, pp. 29-36 (2004), which is incorporated hereinby reference in its entirety).

Statistical analysis and determinations of IC50s were performed by usingPrism-version 3.0 Graphpad Software (San Diego, Calif.). The IC50 valuestested on some representative compounds of the invention were comprisedbetween 12.2 and 151 nM.

Example 9 Interleukin-8 (IL-8) Release Assay Protocol

In order to evaluate the anti-inflammatory effects of novel inhaledcorticosteroids, a selection of these compounds in inhibitingTNFα-induced IL-8 release from human airway smooth muscle cells (ASMCs)was assessed. hASMCs exposed to a variety of inflammatory mediators(Tumor Necrosis Factor (TNF)-α or IL-1β) can undergo phenotypic changesand secrete chemokines and cytokines, which may participate in or evenperpetuate mucosal inflammatory changes via activation and recruitmentof inflammatory cells (see Damera et al., 2009; Howarth et al., 2004;Chung, 2000; Koyama et al., 2000, all of which are incorporated hereinby reference in their entireties).

Current evidence suggests that chemokines and cytokines secretioninduced by inflammatory mediators is inhibited by glucocorticoids inhASMCs and lung fibroblasts (see John et al., 1998; Spoelstra et al.,2002; Tobler et al., 1992, all of which are incorporated herein byreference in their entireties). Steroids may inhibit thecytokine-induced secretion of chemokines by a direct inhibitoryinteraction between activated glucocorticoid receptors and activatedtranscription factors, such as nuclear factor-kappa B and activatorprotein-1 which modulated inflammatory gene expression. In addition,glucocorticoids can regulate chemokine expression by reducing mRNAstability through the rapid induction of potent endogenous inhibitor ofp38 MAP Kinase, MKP-1, which is one of the genes trans-activated bysteroids (see King et al., 2009, which is incorporated herein byreference in its entirety).

Primary human airway smooth muscle cells (ASMCs) were purchased fromLONZA (Basel, CH) and cultured in DMEM medium supplemented with 10%Fetal Bovine Serum, 2 mM glutamine, 100 U penicillin and 100 μg/mlstreptomycin (Invitrogen), in an atmosphere of 95% air and 5% CO₂ at 37°C. ASMCs were seeded in 0.5 ml DMEM containing 10% FBS in 48-well tissueculture plates at the density of 104 cells/well and grown for 24 hoursat 37° C. with 5% CO₂. Then cells were serum starved for 18 hours beforetreatment with different concentration of LAGRA (10-12M-10-6M, finalDMSO concentration 0.1%) for 60 min before stimulation with TNFα (0.1ng/ml as final concentration for ASMCs). After 18 hours incubation inDMEM serum free, the IL8 release in the supernatant was assayed usingELISA kit (Invitrogen). Compound potencies were expresses asconcentration able to inhibit the half maximal (50%) IL8 release [IC50]in the dose-response curve obtained after stimulation with TNFα.

All values stated are mean±standard error of mean (SEM). Compoundpotencies (expresses as half maximal (50%) inhibitory concentration[IC50]) were derived from a four-parameter non-linear iterativecurve-fitting analysis using Prism software (Graph Pad Software, SanDiego, Calif.). Statistical analysis, Sigmoid curves design and analysiswere performed by using Prism software (Graph Pad Software, San Diego,Calif.).

Where a numerical limit or range is stated herein, the endpoints areincluded. Also, all values and subranges within a numerical limit orrange are specifically included as if explicitly written out.

As used herein the words “a” and “an” and the like carry the meaning of“one or more.”

Obviously, numerous modifications and variations of the presentinvention are possible in light of the above teachings. It is thereforeto be understood that, within the scope of the appended claims, theinvention may be practiced otherwise than as specifically describedherein.

All patents and other references mentioned above are incorporated infull herein by this reference, the same as if set forth at length.

The invention claimed is:
 1. A compound of formula (I):

wherein R₁ is linear or branched (C₁-C₁₆)alkyl, linear or branched(C₂-C₁₈)alkenyl, —OR₆, aryl, aryl(C₁-C₁₆)alkyl, —SR₆, —N(R₄)(R₅),(C₃-C₈)cycloalkyl, (C₃-C₈)heterocycloalkyl, or heteroaryl, whereinoptionally one or more hydrogen atoms are replaced by (C₁-C₆)alkyl, andwherein R₄ and R₅ are independently H or linear or branched(C₁-C₆)alkyl, and R₆ is linear or branched (C₁-C₁₆)alkyl; R₂ is aryloptionally substituted by one or more halogen atoms, or apharmaceutically acceptable salt thereof.
 2. A compound orpharmaceutically acceptable salt according to claim 1, whereinstereogenic carbons have a stereochemistry as depicted in formula (I′):


3. A compound or pharmaceutically acceptable salt according to claim 1,wherein R₁ is selected from the group consisting of methyl, isopropyl,ethyl, quindecyl, butyl, hexyl, heptadecenyl, methoxy, methylsulfanyl,isobutyl, isopentyl, tertbutyl, methylamino, dimethylamino, phenyl,cyclopropyl, cyclopentyl, methylpropanoxy, benzyl, piridyl, piperazinyl,piperidinyl, pyrrolidinyl, thiazolidinyl, and furyl; and R₂ isp-chlorophenyl.
 4. A compound or pharmaceutically acceptable saltaccording to claim 2, wherein R₁ is selected from the group consistingof methyl, isopropyl, ethyl, quindecyl, butyl, hexyl, heptadecenyl,methoxy, methylsulfanyl, isobutyl, isopentyl, tertbutyl, methylamino,dimethylamino, phenyl, cyclopropyl, cyclopentyl, methylpropanoxy,benzyl, piridyl, piperazinyl, piperidinyl, pyrrolidinyl, thiazolidinyl,and furyl; and R₂ is p-chlorophenyl.
 5. A compound or pharmaceuticallyacceptable salt according to claim 1, which is a compound selected fromthe group consisting of: isobutyric acid2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethylester; propionic acid 2-[(4aS,4bR,5 S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethylester; hexadecanoic acid2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethylester; octadec-9-enoic acid2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethylester; pentanoic acid 2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethylester; acetic acid2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethylester; benzoic acid2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethylester; methyl carbonate (Methyl formate)2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethylester); S-methyl carbonothioate (or S-methyl methanethioate)2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethylester; 3-methylbutanoic acid2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethylester; pivalic acid2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethylester; 2-phenylacetic acid2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethylester; furan-2-carboxylic acid 2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethylester; cyclopentane-carboxylic acid2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethylester; cyclopropane-carboxylic acid2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethylester; isonicotinic acid2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethylester; isobutyl methyl carbonate2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethylester; hexyl carbonate2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethylester); dimethyl 2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethylcarbamate; methyl2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethylcarbamate; piperazine-1-carboxylic acid2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethylester; thiazolidine-4-carboxylic acid2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethylester; proline,2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6^(a),8,9,9^(a),10,10^(a),10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethylester; and piperidine-4-carboxylic acid,2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethylester; or a pharmaceutically acceptable salt of said compound.
 6. Apharmaceutical composition, comprising a compound or pharmaceuticallyacceptable salt according to claim 1 and one or more pharmaceuticallyacceptable carriers and/or excipients.
 7. A pharmaceutical composition,comprising a compound or pharmaceutically acceptable salt according toclaim 2 and one or more pharmaceutically acceptable carriers and/orexcipients.
 8. A pharmaceutical composition, comprising a compound orpharmaceutically acceptable salt according to claim 3 and one or morepharmaceutically acceptable carriers and/or excipients.
 9. Apharmaceutical composition, comprising a compound or pharmaceuticallyacceptable salt according to claim 4 and one or more pharmaceuticallyacceptable carriers and/or excipients.
 10. A pharmaceutical composition,comprising a compound or pharmaceutically acceptable salt according toclaim 5 and one or more pharmaceutically acceptable carriers and/orexcipients.
 11. A combination, comprising a compound or pharmaceuticallyacceptable salt according to claim 1 and one or more active ingredientsselected from the group consisting of a beta2-agonist, antimuscarinicagent, mitogen-activated protein kinase (P38 MAP kinase) inhibitor,nuclear factor kappa-B kinase subunit beta (IKK2) inhibitor, humanneutrophil elastase (HNE) inhibitor, phosphodiesterase 4 (PDE4)inhibitor, leukotriene modulator, non-steroidal anti-inflammatory agent(NSAID), antitussive agent, expectorant/mucokinetic modulator, peptidemucolytic, inhibitor of Janus kinase (JAK), spleen tyrosine kinaseinhibitor, inhibitor of phosphatidylinositol 3-kinase (PI3K) delta,inhibitor of phosphatidylinositol 3-kinase (PI3K) gamma,M3-antagonist/beta2-agonist (MABA), and M3-antagonist/PDE4-inhibitor(MAPI).
 12. A combination, comprising a compound or pharmaceuticallyacceptable salt according to claim 5 and one or more active ingredientsselected from the group consisting of a beta2-agonist, antimuscarinicagent, mitogen-activated protein kinase (P38 MAP kinase) inhibitor,nuclear factor kappa-B kinase subunit beta (IKK2) inhibitor, humanneutrophil elastase (HNE) inhibitor, phosphodiesterase 4 (PDE4)inhibitor, leukotriene modulator, non-steroidal anti-inflammatory agent(NSAID), antitussive agent, expectorant/mucokinetic modulator, peptidemucolytic, inhibitor of Janus kinase (JAK), spleen tyrosine kinaseinhibitor, inhibitor of phosphatidylinositol 3-kinase (PI3K) delta,inhibitor of phosphatidylinositol 3-kinase (PI3K) gamma,M3-antagonist/beta2-agonist (MABA), and M3-antagonist/PDE4-inhibitor(MAPI).
 13. The compound isobutyric acid2-[(4aS,4bR,5S,6aS,6bR,9aS,10aS,10bS,12S)-8-(4-chloro-phenyl)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,8,9,9a,10,10a,10b,11,12-tetradecahydro-7-oxa-8-aza-pentaleno[2,1-a]phenanthren-6b-yl]-2-oxo-ethylester or a pharmaceutically acceptable salt thereof.
 14. Apharmaceutical composition, comprising a compound or pharmaceuticallyacceptable salt according to claim 12 and one or more pharmaceuticallyacceptable carriers and/or excipients.
 15. A combination, comprising acompound or pharmaceutically acceptable salt according to claim 13 andone or more active ingredients selected from the group consisting of abeta2-agonist, antimuscarinic agent, mitogen-activated protein kinase(P38 MAP kinase) inhibitor, nuclear factor kappa-B kinase subunit beta(IKK2) inhibitor, human neutrophil elastase (HNE) inhibitor,phosphodiesterase 4 (PDE4) inhibitor, leukotriene modulator,non-steroidal anti-inflammatory agent (NSAID), antitussive agent,expectorant/mucokinetic modulator, peptide mucolytic, inhibitor of Januskinase (JAK), spleen tyrosine kinase inhibitor, inhibitor ofphosphatidylinositol 3-kinase (PI3K) delta, inhibitor ofphosphatidylinositol 3-kinase (PI3K) gamma, M3-antagonist/beta2-agonist(MABA), and M3-antagonist/PDE4-inhibitor (MAPI).